This R21 application responds to PA-04-119, replacing 03-080, on Biodefense and Emerging Infectious Diseases Research Opportunities. Cryptosporidiosis is a clinically significant cause of diarrhea. The infection can be life-threatening in individuals with immunodeficiencies because of the severity and chronicity of the diarrhea, and lack of effective therapy. Cryptosporidiosis is usually considered to be wholly confined to the gut, and the mode of transmission to be exclusively fecal-oral. This proposal will explore the contribution, if any, of Cryptosporidiosis to respiratory tract infections. We hypothesize, based on a wealth of data (circumstantial information, human case reports and case series, animal studies, human population-based studies, and human volunteer studies), that respiratory infections with Cryptosporidium occur frequently. However, to our knowledge, no study has ever been conducted to prospectively study this possibility. We have designed a rigorous study of children in Uganda that should either convincingly confirm, or refute, this hypothesis. The outcome of this study will have significant clinical, biological and epidemiological implications, which could be important, given the lack of therapy. For example, the finding of respiratory Cryptosporidiosis may lead to improved clinical care (respiratory support, such as oxygen), and new measures to interrupt transmission (since pulmonary secretions [sputum] may be a source for transmission). How common - and consequently how significant - are infections of the respiratory tract, is unclear. In this revised application, we have strengthened and focused on the clinical study in Uganda, and dropped a prior specific Aim designed to explore the question of respiratory transmission in piglets. Should our project in Uganda show that respiratory Cryptosporidiosis occurs in children, then we will again address that question in a next-step application. The project will focus on attempts to recover Cryptosporidium oocysts from induced sputum of children with acute or persistent diarrhea concurrently experiencing cough, with or without fast breathing. These studies will be performed in children presenting to Mulago Hospital in Kampala, Uganda with acute or persistent diarrhea and cough with or without fast breathing. Mulago Hospital is a site where we have had an ongoing program on diarrhea and malnutrition in children aged 3-59 months for several years, which resulted in several publications. In this resubmission, we have strengthened the study by increasing the sample size, and by proposing to perform more complete genetic analysis of the parasite isolates. This study is important to public health because it may help us to understand if the parasite also causes a lung infection in children. [unreadable] [unreadable] [unreadable]